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before and after 9 months of regular transfusion in a 7-year-old with SCD.
At some point between 190 cm/sec and
240 cm/sec, probably depending on several
variables, it becomes likely that a magnetic
resonance angiogram will indicate significant
arterial stenosis.5
Hydroxyurea (HU) is an antimetabolite
chemotherapeutic agent known, among other
effects, to stimulate fetal hemoglobin production. In the current study, this drug was used
in a prospective phase 2 design (no control
group) to determine the effect of HU given at
maximum tolerated dose (MTD) on TCD
velocities. The authors treated 37 children
with elevated ( ⬎ 50th percentile TCD values
at baseline), 6 with abnormal TCD velocity
who declined to accept the recommended
therapy of chronic transfusion and 31 whose
TCD velocity did not dictate a therapy based
on current evidence. At an MTD of about
27 mg/kg/day, an approximate decrease of
26 to 31 cm/sec was observed at a median
8 months. With therapy, total hemoglobin
increased 20%, fetal hemoglobin more than
doubled, and overall TCD velocities dropped
by about 17%. Although the authors state that
there was no correlation between the magnitude of the TCD velocity decrease and the
hematocrit increase, this is likely a result of the
small sample, as a large body of evidence links
TCD velocity to total hemoglobin or hematocrit in healthy or anemic patients.
This study is an important addition to a
growing body of work that paves the way toward
less invasive or intensive options (than bone marrow transplant or indefinite regular transfusion)
for stroke prevention, at least for some patients.
Although the STOP study suggested that regular transfusion lowered TCD velocity out of proportion to the increase in total hemoglobin that
accompanied the transfusion protocol, this has
been hard to determine with certainty, and the
precise mechanisms whereby transfusion reduces stroke risk are still not known.
Likewise, from the current and other studies with HU, we do not yet know if HU lowers
TCD velocity and, by inference, stroke risk
beyond that expected from the increase in hemoglobin. In the end, it may not matter if it
can be shown in a randomized controlled trial
that, with HU therapy and the accompanying
increase in hemoglobin (and fetal hemoglobin), along with a substantial decrease in TCD
velocity, the stroke risk also goes down. The
study by Zimmerman and colleagues advances
790
the field and helps set the stage for a needed
test of HU for primary stroke prevention in a
randomized clinical trial, ideally with stratification based on baseline TCD velocity.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Fullerton H, Johnston SC, Zhao S, Adams RJ. Declining
rates in Californian children with sickle cell disease. Blood.
2004;104:336-339.
2. Nichols FT, Jones AM, Adams RJ. Stroke Prevention
in Sickle Cell Disease (STOP) Study Guidelines for
Transcranial Doppler Testing. J Neuroimaging. 2001;
11:354-362.
3. Adams RJ, Brambilla DJ, McKie VC, Hsu L, Files B,
Vichinsky E, et al. Transfusion Prevents First Stroke in
Children with Sickle Cell Disease: The “STOP” Study.
N Engl J Med. July 1998;339(1):5-11.
4. Adams RJ and Brambilla DJ for the: Optimizing Stroke
Prevention in Sickle Cell Anemia Investigative Team
(STOP 2). Discontinuing Prophylactic Transfusion to Prevent Stroke in Sickle Cell Disease. N Engl J Med. 2005 Dec
29;353(26):2769-78.
5. Abboud M, Cure‘J, Gallagher D, Hsu L, Wang W,
Zimmerman R, et al. Magnetic Resonance Angiography
(MRA) in Children with Abnormal Transcranial Doppler (TCD) Velocities in the STOP Study. Blood. 2004;
103:2822-2826.
● ● ● IMMUNOBIOLOGY
Comment on Obata et al, page 913
What
does a basophil do?
---------------------------------------------------------------------------------------------------------------Cem Akin
UNIVERSITY OF MICHIGAN
The absence of an animal model deficient in basophils has been a major obstacle in
efforts to delineate the functional significance of basophils in health and disease. In
this issue of Blood, Obata and colleagues describe a monoclonal antibody (Ba103)
which selectively reduces the number of basophils in the peripheral blood and
spleen in mice.
asophils and mast cells share significant
phenotypic and functional properties
(see figure).1 Both cell lineages possess metachromatic granules containing histamine and
proteoglycans, and express the high-affinity
immunoglobulin E (IgE) receptor through
which they can be activated to degranulate and
synthesize inflammatory mediators. These
similarities have led many to consider these 2
cell types to have redundant functional properties. Experiments performed on mast-cell–
B
deficient mice confirmed not only the essential
role of mast cells in allergic inflammation, but
also revealed their important contributions to
a number of innate and acquired immune responses.2,3 However, while mast-cell function
in vivo can be studied by using mice displaying
defective expression of KIT due to loss-offunction mutations in c-kit, a similar model
has not been available for basophils. Development of the Ba103 antibody, which specifically
depletes basophils, should therefore facilitate a
Photomicrograph of a human bone marrow mast cell (left) and a peripheral-blood basophil (right) stained
with Wright-Giemsa. Images were acquired using an Olympus BX41 microscope equipped with a Planar
100ⴛ/1.25 oil lens and an Olympus Q Color 3 camera (Olympus America, Melville, NY) and were processed
with Q Capture Pro version 5.1.1.14 software and Microsoft PowerPoint 2002 (Microsoft, Redmond, WA).
1 AUGUST 2007 I VOLUME 110, NUMBER 3
blood
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
more complete understanding of the functional significance of this cell lineage.
A critical question pertinent to the study
by Obata and colleagues, as raised by a recent
commentary in Blood,4 is whether the cells
recognized and depleted by Ba103 antibody
are really basophils. Ba103 recognizes a subset
of mast cells as well as a second cell type that is
increased by infection with the parasite Nippostrongylus brasiliensis, carries high-affinity
receptors for IgE and IL-3 while lacking other
lineage commitment markers, has the ultrastructural features of basophils, and expresses
the basophil protease MMCP-8 while lacking
other proteases characteristically associated
with eosinophils and neutrophils. It therefore
seems reasonable to accept the latter cell type
recognized by the antibody as a basophil. When
injected intravenously, the antibody selectively
depletes basophils but not mast cells.
The experiments reported by Obata and
colleagues, which compare and contrast mastcell– deficient and basophil-deficient mice,
reveal interesting clues about the contribution
of basophils to various allergic reactions. Basophils have been suspected to contribute to
IgE-mediated immediate hypersensitivity
reactions including anaphylaxis. Interestingly,
the authors show that, in contrast to mast-cell–
deficient mice, basophil-deficient mice display
no significant suppression of IgE-mediated
systemic or local anaphylaxis. Perhaps less
surprisingly, basophil-deficient mice also do
not have any significant inhibition of delayed
contact hypersensitivity.
Basophils have been considered to be important mediators of late-phase allergic reactions, based on their having been found in increased numbers after allergen challenge in
tissues such as lung and skin.5 Experiments by
Obata and colleagues suggest that basophils
play a more pivotal role in initiation rather
than maintenance of IgE-mediated chronic
inflammation, at least in the skin. Human
counterparts of IgE-mediated chronic inflammatory processes may include such common
disorders as atopic dermatitis and allergic
asthma. The value of basophils as targets for
future novel therapies for selected allergic
disorders remains to be explored.
Finally, it could be predicted that the availability of a basophil-deficient animal model
should lead to studies dissecting the role of
basophils in innate immunity and other nonallergic inflammatory processes, ultimately
shedding more light on the age old question of
blood 1 A U G U S T 2 0 0 7 I V O L U M E 1 1 0 , N U M B E R 3
what a basophil does to contribute to healthy
immunologic homeostasis.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
roles of mast cells in biologic responses in vivo. Am J Pathol.
1987;127:191-198.
REFERENCES
4. Lee JJ, McGarry MP. When is a mouse basophil not a
basophil? Blood. 2007;109:859-861.
1. Galli SJ. Mast cells and basophils. Curr Opin Hematol.
2000;7:32-39.
2. Galli SJ, Kitamura Y. Genetically mast-cell-deficient
W/Wv and Sl/Sld mice: their value for the analysis of the
3. Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M,
Tam SY, Galli SJ. Mast cell-deficient W-sash c-kit mutant
Kit W-sh/W-sh mice as a model for investigating mast cell
biology in vivo. Am J Pathol. 2005;167:835-848.
5. Gibbs BF. Human basophils as effectors and immunomodulators of allergic inflammation and innate immunity.
Clin Exp Med. 2005;5:43-49.
● ● ● CLINICAL TRIALS AND OBSERVATIONS
Comment on Darby et al, page 815
An
actuarial GPS for hemophilic longevity
---------------------------------------------------------------------------------------------------------------W. Keith Hoots
UNIVERSITY OF TEXAS-M. D. ANDERSON CANCER CENTER
HIV as a transfusion-transmitted pathogen drastically reduced the lifespan of
people with hemophilia beginning in the 1980s. The question of what would have
been the expected lifespan in this chronic disease, had HIV not happened, has been
the subject of previous epidemiologic reports.
against death from coronary heart disease/
ata from the large, well-characterized
United Kingdom cohort of hemophilia
myocardial infarction is demonstrated, conpatients described by Darby and colleagues in
firming previous observations.1 Not surpristhis issue of Blood provides the most complete
ingly, intracranial hemorrhage (ICH) persists
picture to date of how long HIV-uninfected
as a hemorrhagic mortality risk factor, particuindividuals live and what disease or injury
larly in children younger than 4 years of age.
states are most frequently associated with their Over the 23 years assessed, however, the age of
demise (see figure). The vital status of 6018
those infants dying from ICH became progresHIV-uninfected hemophilia A and B indisively younger, particularly among those with
viduals of all clinical severities was captured
severe disease. As the authors suggest, this
comprehensively, and causes of death for vireffect may result from the introduction of pritually all decedents were ascertained. Without
mary prophylaxis in the United Kingdom in
the confounding of HIV for more than 2 dethe early 1990s, which typically begins at
cades (1977-1999), these
findings provide confirmation of previously
defined mortality risk
factors for hemophilia,
and also elucidate how
the impact of certain of
these risks have evolved
over time.
For example, the
investigators confirm
hepatitis as a mortality
risk factor, but its
weighted impact is not
as striking as previous
reports have implied in
patients with severe
hemophilia A or B. Con- Survival in men in the United Kingdom with hemophilia who were not infected
versely, a protective
with HIV and in the general male population of the United Kingdom in 1999.
effect of hemophilia
See the complete figure in the article beginning on page 815.
D
791
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2007 110: 790-791
doi:10.1182/blood-2007-04-085233
What does a basophil do?
Cem Akin
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